Composition Comprising Biodegradable Hydrating Ceramics for Controlled Drug Delivery

ABSTRACT

The present invention relates to a drug carrier composition comprising i) one or more biodegradable hydrating ceramics ii) one or more expandable agents, and iii) sorbed aqueous medium which in solid form has a ruptured structure. The function of the expandable agent is to create a ruptured structure in the solidified composition, either a foam-like structure or a disintegrated structure where it is split into a large number of parts, particles, units, granules or pieces, so as to obtain an enlarged apparent surface area that is exposed to degradation or erosion upon administration. Suitable substances to obtain this surface enlarging effect are gas-forming agents or swelling agents, gelling agents or disintegrants, here referred to as expandable agents. The expandable agents may be bioresorbable or non-bioresorbable.

PRIORITY DATA

This application is a continuation of U.S. patent application Ser. No.10/576,857, filed on Oct. 17, 2008, which is a United Statesnationalization of Patent Cooperation Treaty ApplicationPCT/EP2004/012060, filed on Oct. 21, 2004, which claims the benefit ofSwedish Patent Application Serial No. 030287-8, filed Oct. 22, 2003, andthe benefit of U.S. Provisional Patent Application Ser. No. 60/561,875,filed on Apr. 14, 2004, each of which are incorporated herein byreference.

FIELD OF THE INVENTION

The present invention relates to novel compositions suitable as carriersfor therapeutically, prophylactically and/or diagnostically activesubstances to the human body or any other mammals. The compositions ofthe invention are based on biodegradable hydrating ceramics and areapplicable for several drug delivery purposes; for example, for targetedtreatment to specific part(s) of the body such as diseased organs or forlocalized treatment of e.g. cancer such as, e.g., prostate cancer e.g.through targeted and local release of hormonal and anti-hormonal agents.

The compositions of the invention, including the active substance (s),can be applied locally with minimally invasive techniques, and asustained (controlled) local release profile of the drug over aprolonged period of time can be obtained.

Such local and sustained delivery of active substances (e.g. drugsubstances) optimises the local concentration-time profile of the activesubstances and their local pharmacological effects, and minimises thesystemic exposure and thus reduces the side-effects, and hence increasesthe safety and utility of the active substance and the pharmaceuticalcomposition containing the active substance. In addition the complianceof the therapy is enhanced.

BACKGROUND OF THE INVENTION

In drug delivery there is a need for improved formulation techniquesthat enables a targeted and/or localised delivery of active drugsubstances to the body. For instance in the drug treatment of tumours orother diseases in local tissues, procedures and formulations to optimisethe local effects of the drugs and reduce the spectrum of side effectsare still needed. Drug release implants that are implanted withminimally invasive surgery are also they attractive since they reducethe need for open surgery.

Ceramic substances like e.g. calcium sulphate have been suggested asimplant materials for controlled release of active substances (see e.g.Royer U.S. Pat. No. 6,391,336, U.S. Pat. No. 6,630,486, US2003/0170307). In order to obtain a slower release of the activesubstance from the ceramics, Royer uses a complexing agent that is apolymeric substance that forms a complex with the active substance,whereby a slower release may be obtained.

However, the present inventors have found another method to adjust therelease rate of the active substance, which method involves sealing ofthe inherent micro-porous structure within the composition in order toensure that the release primarily takes place via erosion orbiodegradation of the implanted composition.

Moreover, a suitable way of controlling the erosion or biodegradationrate is described, based on ensuring a structure of the ceramiccharacterised by an increased surface area towards to surroundingenvironment, whereby the erosion or biodegradation of the composition isincreased (due to the increased apparent surface area). Accordingly, abetter adjustment method is achieved, whereby the primary adjustmentfactor lies in the more open structure, e.g. a ruptured structure like afoam-like structure or a disintegrated structure, obtained in acomposition according to the invention. The increased surface areatowards the body fluids and tissues is achieved using additives herereferred to as expandable agents.

INTRODUCTION Drug Delivery Systems Based on Biodegradable HydratingCeramics

This invention is related to carrier materials of hydrating ceramicswith additives that regulate the drug release rate to span overprolonged periods of time.

The present invention benefits from several of the inherent propertiesof hydrating ceramics. Hydrating ceramics are materials that solidify asa result of chemical reactions between a ceramic powder and water.Common hydrating ceramics are based on calcium silicates (main componentin Portland cement), calcium sulphates (the main component of gypsum),and calcium phosphates (e.g. hydroxyapatite, the mineral of bonetissue). The hydrating ceramics are often used as fine-grained powders,which are mixed with water to achieve mouldable pastes, and additives tooptimise properties like viscosity and curing time.

As the powder is mixed with water, chemical processes take placeinvolving the formation of hydrate phases containing chemically bondedwater. The formed hydrates constitute the binding phase that holdstogether (cements) the hence formed solid material. The hydrationprocess and thereby the properties of the hydrate materials iscontrolled by additives.

It is inherent to the hydrating ceramics, that they show some degree ofmicro-porosity after curing. This is because of the limited degree ofhydrate formation and water absorption during the hydration. Dependingon type of ceramic, and the amount of water added, as well as theoriginal grain size of the ceramic powder, the pore size of a curedceramic is normally between 1 and 10 microns and the total porosity inthe order of 10-30%. Pores between 10 and 100 microns and porositiesbetween 30 and 50% are also conceivable. This porosity is referred to asthe micro-porosity in the present context. The micro-porosityconstitutes a structure of openings between the original ceramic grains.This micro-porosity allows for water to be sorbed by capillary forcesinto the hydrophilic material and thereby creates a diffusion path forwater solvable or soluble molecules. There is however no or limitedrheological flow through the micro-porosity, and tissues cannot growinto it.

Several biodegradable ceramic compositions have been developed for drugdelivery purposes. Either the drug is added as a powder, suspension,solution, emulsion or liquid to a paste of ceramic powder and water, andis embedded in the ceramic as it cures. Alternatively, a porous curedbody of the ceramic is soaked in a liquid that contains the dissolveddrug.

In orthopedics hydroxyapatite, calcium phosphate or calcium sulphatesystems are used in the form of beads granules, scaffolds and mouldablein-vivo curing pastes, both to provide mechanical stability at the siteof a fracture, but also to leak therapeutic substances, e.g. antibioticsand bone growth factors, to surrounding tissue.

The biodegradable ceramics have many favourable properties as carriersfor drugs in slow release applications, such as non-toxic componentsnormally occurring in living tissues, a high degree of biocompatibility,ease of production, etc.

Resorbable calcium phosphate based ceramics are described in U.S. Pat.No. 6,027,742. Biodegradable calcium sulphate materials are described inWO 03/082158, and WO 00/45734.

However, the release rate of drug substances from these ceramic carriersis difficult to tune. For both calcium phosphate and calcium sulphatebased drug delivery compositions, the release time span generallybecomes too high for many drug systems, in the order of 1-3 weeks orless. The present invention provides compositions, wherein the releaserate can be prolonged to 1-6 months or more.

Normally, the drug release rate from a ceramic implant is controlled bytwo factors: First, the release of drugs through the water filledmicro-porosity of the implanted composition. The water filledmicro-porosity is a path for drugs and a solvable drug may betransported from the implant interior to the surrounding tissues, bye.g. diffusion, convection or flow. Second, the release rate is causedby the degradation or erosion of the implant itself, which as itproceeds exposes the implant interior and the encapsulated drug to theenvironment.

The present invention provides compositions, which provide prolongeddrug release rates from biodegradable implants based on hydratingceramics, wherein the release mechanism primarily is based on theoverall erosion of the ceramics.

SUMMARY OF THE INVENTION

The present invention provides in a first aspect, a drug carriercomposition comprising

i) one or more biodegradable hydrating ceramicsii) one or more expandable agents, andiii) sorbed aqueous mediumwhich in solid form has a ruptured structure.

The drug carrier composition is the basis in a pharmaceuticalcomposition of the invention. Accordingly, in a second aspect, theinvention relates to a pharmaceutical composition comprising

i) one or more biodegradable hydrating ceramicsii) one or more expandable agents,iii) sorbed aqueous medium, andiv) one or more therapeutically, prophylactically and/or diagnosticallyactive substances, which in solid form has a ruptured structure.

As apparent from the above, the drug carrier composition as well as thepharmaceutical composition may be in fluid, liquid, semi-solid or solidform. As will be explained in detail herein, a composition is suitablyapplied in a paste or another semi-solid form (preferably injectableform), but it must relatively quickly solidify upon administration inorder to remain at the desired site (e.g. organ). Thesolidification/hydration may take place inside or out-side of the body.Accordingly, within the scope of the present invention are both theinjectable compositions as well as the solidified compositions.

A practical use of the compositions of the invention may be toinitialize the hydrating process immediately before administration to apatient. Accordingly, a composition containing the ingredients in powderor particulate form is also within the scope of the present inventionand intended to be admixed with water or an aqueous medium immediatelybefore administration. Thus, in a third aspect, the invention relates toa composition in particulate form for use in the preparation of a drugcarrier composition as defined in any of claims 1-24 or a pharmaceuticalcomposition as defined in any of claims 25-69, the compositioncomprising

i) one or more biodegradable hydrating ceramics in powder formii) one or more expandable agents, andiii) optionally, one or more therapeutically, prophylactically and/ordiagnostically active substances.

The present invention also provides a method for preparation of apharmaceutical composition as defined in any of claims 25-69.

As mentioned above the invention relates to compositions, which aresuitable for local drug delivery over prolonged periods of time such as,e.g., in the order of 1-6 months or longer. As an example this can beused for treatment of prostate cancer through local release of hormonaland anti-hormonal agents, including for example androgens andanti-androgens, in the prostate gland.

The present invention provides a mouldable pasty or putty containing thedrugs of choice, which can be positioned with standard surgicalinstruments (needles, tubings, etc) at the selected site in the body.The paste may posses a high X-ray, ultrasonic and magnetic resonancevisibility. Once positioned, the biodegradable composition solidifies invivo and hence forms an implant of mechanical integrity. The implant(i.e. the solidified pharmaceutical composition) provides a sustainedrelease of the therapeutic agents for a prolonged period of time (1-6months or more) to the surrounding tissues.

The treatment composition prior to solidification consists essentiallyof a hydrating ceramic powder, the active substances of choice,expandable agents, like gas-forming agents or disintegrants to enhancethe external surface exposed to the tissues, an aqueous medium and ifnecessary pore-sealing agents and other additives. After solidification,the implant is characterised by a matrix based on hydrated ceramics, amicro-porosity that is largely filled (sealing of the pores) to preventcommunication and exchange of substances with the implant interior, andthe selected drug being encapsulated in the implant.

DETAILED DISCLOSURE OF THE INVENTION

As mentioned above, the present invention provides a drug carriercomposition comprising

i) one or more biodegradable hydrating ceramicsii) one or more expandable agents; andiii) sorbed aqueous mediumwhich in solid form has a ruptured structure.

A ruptured structure is an open structure, wherein the inner and outersurfaces are interrupted by openings or fractures. Examples arefoam-like structures created by expandable agents like gas-formingagents, or disintegrated structures created by disintegrants.

The one or more expandable agents may either contribute to the rupturedstructure by creating a foam-like structure with openings, wherein atleast 50% or more have a largest width of at least about 0.1 mm, or bydisintegration of solidified material into two or more parts. These twoor more parts have an external surface area that is at least about twiceas large as that of the composition before disintegration such as, e.g.at least about ten times as large, at least about a hundred times aslarge, or about a thousand times as large or more. Openings in thefoam-like structure can be seen by microscopy (cf. FIG. 2 herein). Theopenings may of course be of varying size, but it is desirable that aleast every second (corresponding to 50%) on an average basis has alargest width of at least about 0.1 mm. Especially, at least 60% (6 outof 10 on an average basis) such as, e.g., at least 70% (7 out of 10 onan average basis), at least 75% (15 out of 20 on an average basis), atleast 80% (8 out of 10 on an average basis), at least 85% (17 out of 20on an average basis) or at least 90% (9 out of 10 on an average basis)of the openings have a largest width of at least about 0.1 mm. Inpreferred aspects, the openings have a largest width of at least about0.2 mm such as, e.g. at least about 0.3 mm, at least about 0.4 mm, atleast about 0.5 mm, or they have a largest width of at least about 0.6mm such as, e.g. at least about 0.8 mm, at least about 1.0 mm, or fromabout 0.1 mm to about 2 mm such as, e.g., from about 0.3 mm to about 1.5mm or from about 0.5 mm to about 1.5 mm. Alternatively, the surface areaof an opening in cross sectional view having a largest width of at leastabout 0.1 mm is at least about 3×10⁻⁸ m² such as, e.g. at least about5×10⁻⁸ m², at least 1×10⁻⁷ m², at least about 5×10⁻⁷ m², at least about1×10⁻6 m², or about 5×10⁻⁶ m² or more.

In an embodiment of the invention the drug carrier composition furthercomprises one or more therapeutically, prophylactically and/ordiagnostically active substances. In a preferred embodiment of theinvention the therapeutically, prophylactically and/or diagnosticallyactive substance in the pharmaceutical composition is an anti-canceragent. The active substance may be homogeneously dispersed in thebiodegradable hydrating ceramic.

A drug carrier composition and a pharmaceutical composition according tothe invention may have a shape like e.g. beads, pellets, tubes,polygons, spheres, stars, cubes, etc.

In the present context the term “controlled release” is used synonymouswith the terms “sustained release”, “modified release”, and “prolongedrelease”, and intended to mean a release of an active substanceaccording to a predetermined pattern, e.g. zero order release, or otherorders of release, with or without an initial burst release and/or aninitial lag time before start of a release.

In the present context the term “release” is used synonymous with theterm “delivery”.

In the following is given details with respect to the individualingredient.

The Hydrating Ceramic

According to the invention, an implant for sustained drug delivery isachieved from a composition based one or several hydrating ceramics.Suitable biodegradable hydrating ceramic for use in a composition of theinvention is selected from the group consisting of non-hydrated orhydrated calcium sulphate, calcium phosphate, calcium carbonate, calciumfluoride, calcium silicate, magnesium sulphate, magnesium phosphate,magnesium carbonate, magnesium fluoride, magnesium silicate, bariumsulphate, barium phosphate, barium carbonate, barium fluoride, bariumsilicate, or mixtures thereof.

Of prime interest are calcium sulphates such as non-hydrated or hydratedcalcium sulphate. In its most basic form, the hydrating ceramic of thecomposition is calcium sulphate. The calcium sulphate may be of thealfa- or beta-structure and be non-hydrated, hemihydrates or fullyhydrated.

However, as described above also calcium phosphates, calcium carbonates,calcium fluorides and calcium silicates, alone or in combination, andwith various amounts of bonded water, are relevant to the invention. Ina more general form of the invention, the calcium of these ceramics maybe replaced by magnesium or barium. Any combination of these ceramics isof relevance to the invention.

The biodegradable hydrating ceramic is added to the composition in theform of a powder such as a fine-grained powder, with a mean particlesize of at the most about 75 um such as, e.g., at the most about 50 um,at the most about 25 um or at the most about 10 um.

According to the invention, the biodegradable hydrating ceramic isnormally used with additives that regulate the release rate byoptimising the micro-porosity of the cured implant (pore-sealing agents)and the external surface of the implant (by use of expandable agents),which is exposed to the surroundings. A reduced micro-porosity reducesthe leaching of drugs from the implant through water that penetrates theporosity. An increased surface of the implant increases its erosion rateand reduces the sensitivity to dimensions of the implant.

Any concentration of hydrated ceramic in the treatment compositionfalling between 10 and 99 vol. %, as measured on the solidified implant,is of relevance to the invention. Most preferably the solidifiedtreatment composition contains between 70 and 95 vol. % of hydratedceramic.

A drug carrier composition according to the invention may be constitutedin such a way, that the hydrating ceramics does not cure while thecomposition is mixed or during an implantation by e.g. injection in apatient, but readily cures at body temperature after injection. The drugcarrier composition may solidify after a suitable time period of about20 min or less such as, e.g. about 15 min or less, about 10 min or lessor about 5 min or less when stored at 37° C. Optionally the compositionmay be prepared and cured outside the body, and implanted as solidpieces

Optionally, the composition of the invention also contains non-hydratingceramic and metallic additives. The purpose of such additional componentis increased radio-opacity, improved mechanical strength orsolidification rate control. Established radio-opacity additives arebarium salts or metals such as gold, zirconium or tantalum and theiroxides.

Release Rate Control

Normally, the drug release rate from a cured hydrating ceramic implantis basically controlled by two factors: First, the leaching of watersolvable drugs from the implant interior to the surroundings caused by atransport of water through the micro-porosity of the implant. Second,the degradation of the ceramic implant itself in the environment of theimplantation site, which over time erodes the material and exposes theimplant interior and new drug to the environment.

The erosion rate of the ceramic material is controlled by numerousfactors including: the type ceramic material and its solubility in abody liquid, the size of the surface exposed to the tissue and thetype/composition of tissues and body fluids that the implant issurrounded by. Different hydrating ceramics differ strongly in theirinherent chemical stability and degradation rate; calcium sulphates aregenerally considered as quickly degradable (4-6 weeks in bone tissue),calcium phosphates as more stable (many months or years depending on thetype of calcium phosphate), whereas hydrated calcium silicates are evenmore stable.

The surface exposed to the body environment may be controlled bycreating openings of sufficient size for tissue and cells to invade theimplant, i.e. larger than 100 microns, alternatively with an additivethat disintegrates and splits the implant into numerous pieces/segmentsthat act as multiple release sites. The openings may be created by theaction of expandable agents.

Expandable Agents

As mentioned above, a drug carrier composition according to theinvention comprises one or more expandable agents. The function of theexpandable agent is to create a ruptured structure in the solidifiedcomposition, either a foam-like structure or a disintegrated structurewhere it is spit into a large number of parts, particles, units,granules or pieces, so as to obtain an enlarged apparent surface areathat is exposed to degradation or erosion upon administration. Suitablesubstances to obtain this surface enlarging effect are gas-formingagents or swelling agents, gelling agents or disintegrants, herereferred to as expandable agents. The expandable agents may bebioresorbable or non-bioresorbable.

To obtain a controllable release rate through erosion of theceramic-based carrier material, a large surface area envisaging thesurrounding environment is essential. This area is the sum of the outerarea A_(out), or the geometrical area of the implant, defining theextension of the implant in the body; and the inner area A_(in) frome.g. a foam structure or a disintegrated structure of multiple parts orparticles caused by e.g. a swelling additive in the structure. For acontrollable release, the outer area A_(out) must be much smaller thanthe inner area, i.e. A_(out)<<A_(in).

Examples of expandable agents that are gas-forming agents are e.g.alkali metal carbonates including sodium carbonate and potassiumcarbonates; alkali metal hydrogen carbonates including sodium hydrogencarbonate and potassium hydrogen carbonate; and hydrogen peroxide.

Suitable examples of expandable agents that are swelling agents, gellingagents or disintegrants are e.g. alginic acid, alginates, cellulose andcellulose derivatives e.g. of various molecular weights, includingcalcium carboxymethylcellulose, sodium carboxymethylcellulose,crospovidone, hydroxypropylcellulose, hydroxypropylmethylcellulose(HPMC), low substituted hydroxypropylcellulose (L-HPC), microcrystallinecellulose, pectins, polyethylene glycols, polyethylene oxides,polyvinylpyrrolidone, starches e.g. of various molecular weightsincluding corn starch, rice starch, potato starch, and mixtures thereof.

A mixture of gas-forming agent(s) and swelling agent(s), gellingagent(s) or disintegrant(s) may also be suitable for use in the presentcontext.

Normally, the concentration of the expandable agent in the compositionis at least about 0.1% w/w such as, e.g., at least about 0.2% w/w, atleast about 0.3% w/w, at least about 0.4% w/w or at least about 0.5% w/wor from about 0.1% to about 10% w/w such as, e.g., from about 0.1% toabout 5% w/w, from about 0.1% to about 2.5% w/w or from about 0.1% toabout 1% w/w.

In an embodiment of the invention the one or more biodegradablehydrating ceramics and the expandable agent are homogeneously dispersedin water so that the hydrating ceramic and/or the expandable agent sorbswater.

With respect to the final water content, a composition according to theinvention normally has a concentration of sorbed aqueous medium of atthe most about 60% w/w such as, e.g., at the most about 50% w/w, at themost about 45% w/w, at the most about 40% w/w or at the most about 30%w/w of the total composition.

In the present context, the term “sorption” is uses as a commonexpression for either “adsorption” or “absorption” or both.

Microporosity

As mentioned above, the one or more biodegradable hydrating ceramics mayhave a microporous structure. In a preferred embodiment of theinvention, at least part of the microporous structures is sealed with apore-sealing agent. More specifically, at least 50% such as, e.g., 60%or more, 70% or more, 80% or more or 90% or more of the microporousstructures is sealed with a pore-sealing agent.

Examples of pore-sealing agents suitable for use in the present contextare hydrophobic agents, hydrophilic agents and water-absorbing agents.Pore-sealing agents that reduce the micro-porosity and produce a sealingof the ceramic implant are:

-   -   Hydrophobic or poorly water soluble additives added to the        treatment composition as liquids, suspensions or dispersions        that fill the micro-porosity and prevent water from penetrating        and leach the drugs from the implant. Examples of such additives        are: oils, rubbers, waxes, hydrocarbons, cellulose derivatives,        etc. specific examples are silicon oil or silicon rubber, waxes,        paraffinic hydrocarbons, polyvinylalcohols, ethyl cellulose.        Amounts of these additives up to 30 vol. %, as measured on the        cured implant is of relevance to the invention.    -   Water soluble or hydrophilic additives that fill porosity with a        thick or gel like consistency and prevent the water circulation        through the implant. Examples of such additives are:        methylcellulose, hyaluronic acid, dextran, polyethylene glycol        (PEG). Amounts of these additives up to 30 vol. %, as measured        on the cured implant is of relevance to the invention.    -   Water absorbing agents, which bind the excessive water that is        not consumed in the hydration of the ceramic, may be highly        water absorbing ionic salt additives. Examples of such additives        are: water glasses, silica gel, sodium phosphate, etc. Amounts        of these additives up to 30 vol. %, as measured on the cured        implant is of relevance to the invention.    -   Hydrating ceramics with a high water absorption during        hydration. Most interesting to the invention are calcium        silicates and calcium aluminates. However, also additions of        calcium phosphates, calcium carbonates, calcium fluorides and        calcium silicates, alone or in combination are relevant to the        invention. The calcium may be replaced by magnesium or barium.        Amounts of these additives up to 30 vol. %, as measured on the        cured implant is of relevance to the invention.

Normally, the concentration of the pore-sealing agent in the compositionis about 30% w/w or less such as, e.g., about 25% w/w or less or about20% or less in the final composition.

Optionally, the composition may also contain rheology control additivessuch as poly-carboxylic acids or poly-acrylic acids; methylcellulose,dextran or hyaluronic acid.

Optionally, the treatment composition may also contain a bio-adhesivecomponent, such as suitable polymer, which helps the therapeutic agentto stay adhered to the surrounding tissue over a prolonged period oftime.

The composition contains water or an aqueous medium as a principalsolvent.

Property Profile of Composition

Apart from carrying and releasing the therapeutic agent, the compositionof the invention is such that it also provides a property profileincluding:

-   -   a viscosity allowing injectability through standard syringes,        needles, tubing systems and cannulae for minimally invasive        application of the composition to the selected site;    -   in-situ solidification properties so that the composition        solidifies within 5 to 20 minutes after final mixing providing        increased mechanical and chemical resistance after application        at the selected site to make the composition stay constrained        and resist the movements of the tissues and the flow of body        fluids.    -   a high visibility with radioscopy (X-ray), ultrasonic and        magnetic resonance imaging techniques. Monitoring facilitates        the accurate application of the treatment composition at the        selected site, as well as the continuous observation of the        biodegradation rate for individualised dosing.    -   a sustained release profile for the active substance; e.g. for        the treatment of prostate cancer a suitable substance is        2-hydroxy-flutamide that fulfils the therapeutic concentration        which is within the interval 0.001-1000 uM, preferably 0.01-100        uM or more preferably 0.05-5.0 uM, and the treatment time for        one dose is at least 3-6 months or more.

In a specific embodiment the active substance is controlled releasedfrom the composition. More specifically, at the most about 10% w/w ofthe active substance contained in the composition is released 5 days ormore after implantation to a human, and/or at the most about 50% w/w ofthe active substance contained in the composition is released 1 month ormore after implantation to a human, and/or at the most about 75% w/w ofthe active substance contained in the composition is released 1.5 monthor more such as, e.g., 2 month or more after implantation to a human,and/or at most about 100% w/w of the active substance contained in thecomposition is released 2 month or more such as 2.5 month or more or 3month or more after implantation to a human.

In an alternative embodiment at the most about 10% w/w of the activesubstance contained in the composition is released after 2 days ormore—when tested in an in vitro dissolution test according to Ph.Eur.(paddle), and/or at the most about 50% w/w of the active substancecontained in the composition is released after 1 month or more—whentested in an in vitro dissolution test according to Ph.Eur. (paddle),and/or at the most about 75% w/w of the active substance contained inthe composition is released after 1.5 month or more such as, e.g., 2month or more—when tested in an in vitro dissolution test according toPh.Eur. (paddle), and/or at the most about 100% w/w of the activesubstance contained in the composition is released after 2 month or moresuch as 2.5 month or more or 3 month or more—when tested in an in vitrodissolution test according to Ph.Eur. (paddle).

Drugs of Relevance to the Invention

The invention is also applicable to therapeutic agents in a broad sense,including androgens or derivates thereof (e.g. testosterone),antiandrogens (cyproteron, flutamide, hydroxyflutamide, bicalutamide,nilutamide) or derivatives thereof, oestrogens or derivates thereof,anti-oestrogens (e.g. tamoxifen, toremifen) or derivates thereof,gestagens or derivates thereof, antigestagens or derivates thereof,oligonucleotides, progestagens or derivates thereof,gonadotropin-releasing hormone or analogues or derivates thereof,gonadotropin inhibitors or derivates thereof, adrenal and prostateenzyme synthesis inhibitors (such as alpha-reductase inhibitors),membrane efflux and membrane transport proteins (such as PSC 833,verapamil), and other cytostatic agents, immune system modulators andangiogenesis inhibitors alone or in combinations.

The invention also includes any other suitable pharmaceutical agentsapplied in soft tissues or organs for local or systemic sustained drugrelease. The sustained drug release compositions of the invention canalso be explored in other treatments e.g.: pain, neurological diseases(Alzheimer, Parkinson), autoimmune diseases, immunological diseases, anddiseases responding to immunological and immunomodulating therapy(hepatitis, MS, tumours), infections, inflammations, metabolic diseases,obesitas, diseases in the uro-genital tract, cardiovascular diseases(including blood pressure), hematopoietic, anticoagulant, thrombolyticand antiplatelet diseases, chemotherapy of parasitic infections,microbial diseases and neoplastic diseases, hypercholesterolemia,dyslipidemia, hematopoetic diseases, respiratory diseases (asthma,chronical lung obstruction), diseases of the kidney, gastrointestinaldiseases, liver diseases, hormonal disruption, replacement andsubstitution, vitamins replacement and substitution. Examples of activedrug substances from various pharmacolocial classes for the use in thepresent clinical context include e.g. antibacterial agents,antihistamines and decongestants, anti-inflammatory agents,antiparasitics, antivirals, local anaesthetics, antifungals,amoebicidals or trichomonocidal agents, analgesics, antianxiety agents,anticlotting agents, antiarthritics, antiasthmatics, anticoagulants,anticonvulsants, antidepressants, antidiabetics, antiglaucoma agents,antimalarials, antimicrobials, antineoplastics, antiobesity agents,antipsychotics, antihypertensives, auto-immune disorder agents,anti-impotence agents, anti-Parkinsonism agents, anti-Alzheimers agents,antipyretics, anticholinergics, anti-ulcer agents, anorexics,beta-blockers, beta-2 agonists, alpha receptor antagonists and agonists,blood glucose-lowering agents, bronchodilators, agents with effect onthe central nervous system, cardiovascular agents, cognitive enhancers,contraceptives, cholesterol-reducing agents, agents againstdyslipidemia, cytostatics, diuretics, germicidals, H-2 blockers,hormonal agents, anti-hormonal agents, hypnotic agents, inotropics,muscle relaxants, muscle contractants, physic energizers, sedatives,sympathomimetics, vasodilators, vasoconstrictors, tranquilizers,electrolyte supplements, vitamins, uricosurics, cardiac glycosides,membrane efflux inhibitors, membrane transport protein inhibitors,expectorants, purgatives, contrast materials, radiopharmaceutical,imaging agents, peptides, enzymes, growth factors, vaccines, mineraltrace elements, etc.

The therapeutically, prophylactically and/or diagnostically active drugsubstance(s) may also be in the form of a pharmaceutically acceptablesalt, solvate or complex thereof or in any suitable crystalline oramorphous form or in the form of a prodrug.

The drug load of the implant composition, i.e. the amount of activesubstance in the composition, can vary within wide limits. Theconcentration of the active substance in the composition may be in therange from about 0.01% w/w to about 50% w/w such as, e.g. from about0.01% w/w to about 40% w/w, from about 0.05% w/w to about 30% w/w, fromabout 0.05% w/w to about 20% w/w or preferably from about 0.1% w/w toabout 10% w/w, of the composition. Some active substances may thussuitably be present in an amount of up to about 50% w/w of thecomposition, whereas the active substance may also, depending on thenature and strength of the active substance in question, be present inthe composition in much smaller amounts.

Optionally, the therapeutic agents are mixed with a bio-degradablepolymeric substances such as: polylactic acid, polyglycolic acid,poly(lactic-co-glycolic) acid, polyanhydrides, blockpolymers,poly(orthoesters), poly(p-dioxanone), poly(alpha hydroxy butyric acid),and their co-polymers with polyethylene oxide or polypropylene oxide,and any mixtures thereof. The purpose of these polymer additives is tocontrol the biodegradation rate and the drug release rate. In a generalform of the invention any biodegradable polymeric additive, which mayserve as carrier for a therapeutic agent is of relevance. Thedrug-biodegradable polymer system may be added to the composition in theform of liquid, large particles or as small nano- and micro-particles.

Method for Preparing a Composition According to the Invention

In a specific aspect, the invention relates to a method for thepreparation of a pharmaceutical composition as defined in any of claims25-69, which method comprises dispersing a mixture of

i) one or more biodegradable hydrating ceramics in powder form, andii) one or more expandable agents, iniii) an aqueous medium,wherein either the mixture of i) and ii), or iii) further comprisesiv) one or more therapeutically, prophylactically and/or diagnosticallyactive substances.The pharmaceutical composition is an injectable and in vivo solidifyingcomposition for controlled release of the active substance.

Other embodiments appear from the appended claims to which reference ismade. The details and particulars mentioned above under the main aspectapply mutatis mutandis to the other aspects of the invention.

Example Prostate Cancer

A specific example of the usefulness of a composition according to thepresent invention is a composition containing an anti-cancer drugsubstance without limiting the invention to use in the treatment ofprostate cancer or to compositions containing hydroxyflutamide as anactive substance. The principal application of the present invention isfor treatment of prostate diseases, primarily cancer and prostatehyperplasia (enlarged prostate). Some background to this field isprovided first.

There are malignant and non-malignant tumours. Cancers and Sarcomas aremalignant tumours, characterised by a non-controlled cell growth, and bythe ability to invade and seed metastasis.

For men, prostate cancer is the most common type of cancer; it is todaya leading lethal malignancy with increasing incidence worldwide.Prostate cancer patients can develop a resistance to anti-hormonaltreatments (a so called androgen-independent disease), which remains themain obstacle to improved life expectancy. Existing systemic hormonaltreatments only improve survival with a few years.

The function of the prostate gland is to secrete the milky substance ofseminal fluid. Before puberty, this function does not exist and thegland is very small. Unlike many organs the growth of the prostate glandcontinues throughout the lifespan, often resulting in a benign prostatichyperplasia of the gland.

The prostate is located anteriorly to the rectum. Above the prostategland is the urinary bladder and below the urogenital diaphragm. Theseminal vesicles form the ejaculatory ducts and enter the gland in aposterio-lateral direction and emerge in the urethra in approximatelythe middle of the gland. The gland is covered by a fibrotic capsule andhas an elastic consistency.

The frequency of prostate cancer has stimulated the search for improvedtherapeutic agents and treatment procedures, e.g. novel anti-androgenicagents, prostate cancer gene therapy, immunotherapy. An important factorfor a successful outcome of many of these new, or the more establishedtherapeutic approaches, is ensuring sufficient local and sustainedeffect of the therapeutic substance within the tumour tissue, whileminimising systemic effects.

Treatment Options

The treatment options for prostate cancer can be grouped into four broadcategories: observation (for elderly patients and those withco-morbidities), anti-cancer therapy (for example hormone oranti-hormone, anti-metabolites, cytotoxic agents), surgery (radicalprostatectomy), and radiotherapy (external-beam radiotherapy,brachytherapy, i.e. local placement of radioactive sources, or both).

The prostate is a hormone-responsive organ; this is the basis fortreatments that either reduce serum and intracellular testosterone orblock the actions of this hormone. Many anti-hormonal agents act toinhibit production of or block the action of testosterone. Examples ofhormonal or ant-hormonal agents are oestrogens, progestagens,gonadotropin-releasing hormone analogues, adrenal and prostate enzymesynthesis inhibitors, inhibitors of membrane efflux and membranetransport proteins, gestagenes and antigestagenes, androgens andantiandrogens. Common is a combination of an antiandrogen with agonadotropin-releasing hormone analogue to provide total blockade ofandrogens.

Also alternative methods for treating prostate diseases have beendeveloped. Some are based on the intramuscular or subcutaneousapplication of sustained drug delivery depot formulations containing theselected drug as one component. Also repeated intraprostatic andintralesional injection of therapeutic compounds has been described.These methods have the disadvantages of producing either prolongedsystemic exposure to high doses of formulations, or to requirerepetitive injections over substantial periods of time, respectively.

Disadvantages with present hormonal/anti-hormonal therapies of prostatecancer Common side-effects of systemically administeredhormonal/anti-hormonal therapies are hot flushes, loss of libido orerectile function, weight gain, gynaecomastia, liver inflammation, andosteoporosis. These troublesome side effects remain major obstacles tohormonal dosing, and must be balanced against the long-term benefits.

The most commonly used oral antiandrogen therapy today is biclutamide(Casodex). It is used alone for early non-metastatic disease. The sideeffect spectrum of all clinically used antiandrogens includes diarrhea,breast enlargement, nausea, impotence, decreased libido, abdominal pain,flatulence, tiredness, asthenia, osteoporosis and sweating, and adecreased quality of life.

These side effects of the anti-cancer chemotherapy are to a major extentdue to high levels of the active drug in the systemic circulation anddifferent tissues outside the cancer tissue in the prostate.Importantly, none of these side effects are related to, or mediated by,the local drug action in the prostate tissue.

In view of the methods described above for treatment of prostate cancer,there is a need for improved procedures and formulations to optimise theeffects of hormonal/anti-hormonal and other anticancer agents. Suchbetter treatments would reduce the need for surgery andradio-treatments, and minimise the spectrum of side effects.

However, also the drug treatment of many other types of cancer as wellas other diseases in soft tissue in humans and any other mammals wouldbenefit from the sustained release formulation of the invention, bothfor local and systemic delivery.

Now focusing on a suitable active substance for use in the treatment ofprostate cancer, 2-hydroxy-flutamide. In a pharmaceutical composition ofthe invention a controlled release profile for 2-hydroxy-flutamide,shall fulfil the therapeutic concentration, which is within the interval0.001-1000 uM, preferably 0.01-100 uM or more preferably 0.05-5.0.uM,and the treatment time for one dose is at least 3-6 months or more.

The active substance may be implanted into the prostate tissue throughthe urethra by conventional cystoscopy or other technique forinjections/implantation such as ultrasound, MR (magnetic resonance),X-ray, CT (computer tomography), manual guidance through the rectum,etc.

The treatment response may be monitored by assaying PSA (prostatespecific antigen) in plasma (a well-established bio-marker for thisdisease), i.e. the same diagnostic systems used in routine practice inthe management and follow-up of patients with prostate cancer. If alocal treatment fails to lower the PSA level, the risk of metastatictissue increases.

The following examples are intended to illustrate the invention withoutlimiting it thereto.

BRIEF DESCRIPTION OF DRAWINGS

The invention will now be exemplified in further detail below withreference to the enclosed drawings.

FIG. 1: Optical microscopy image of polished plat surface of a calciumsulphate-water pellet as in Example 1. At a magnification of 50× noporosity is visible.

FIG. 2: Optical microscopy image of polished surface of a calciumsulphate-water pellet with sodium bicarbonate as in Example 5. At amagnification of 50× openings are visible.

FIG. 3: Graph showing the plasma concentrations of 2-hydroxyflutamide indog plasma after three different doses of 2-hydroxyflutamide (H2, H3 andH4) in a calcium sulphate-water implant in dog prostate tissue. One dog(H1) was used as control and was dosed an implant without2-hydroxyflutamide.

EXAMPLES Example 1 Compositions Having Varying Water Content

Compositions based on calcium sulphate, water and hydroxyflutamide wereprepared by mixing powder of calcium sulphate hemi-hydrate (CaSO4-½H₂O)from Riedel-deHaën (CAS-no 10034-76-1), laboratory de-ionised water andpowder of 2-hydroxyflutamid (HF). The compositions contain thefollowing:

Composition 1 concentration in the final Ingredient amount (g)composition (% w/w) Calcium sulphate 0.396 79.2 Hydroxyflutamide 0.0040.8 Water 0.100 20.0

Composition 2 concentration in the final Ingredient amount (g)composition (% w/w) Calcium sulphate 0.296 59.2 Hydroxyflutamide 0.0040.8 Water 0.200 40.0

Pastes were prepared with two different water contents: Calcium sulphatewith 20% water and 0.8% of HF, and calcium sulphate with 40% water and0.8% of HF.

The materials were prepared as pellets with a size of diameter 4 mm andthickness 1.0 mm. Three pellets were prepared of each composition. Thepellets were left to harden for 1 hr after preparation. Each pellet wasincubated individually in a tube containing 10 ml of saline solution (9mg/ml concentration) and kept in a water bath at 37° C. for a total of14 days. A sample of 0.5 ml of the saline was taken every 24 hours andthe volume was replaced with 0.5 ml of fresh saline solution. Theconcentration of HF in the saline solution was measured in each samplewith a HPLC-method with UV-detection.

The overall porosities of both compositions were between 30 and 50% asestimated with a Zeiss Scanning electron microscope on cross-sections ofdried samples.

After 4 days, the more water rich composition (40%) had released anaverage of 24%, and the samples with 20% water had released about 20% ofthe HF. However, after 15 days both compositions had released about 50%of their HF.

During these 15 days the degradation of the calcium sulphate isnegligible.

In conclusion, the variation in water content has a small but measurableeffect on the release rate during the initial stage of the release.Higher water content presumably produces a slightly higher porosity,which might explain this initial difference. However, no difference inporosity could be measured. After significant amounts of HF have beenreleased, there is no more any significant difference in the releaserate.

It is believed that the release is largely controlled by diffusionthrough the porosity.

Example 2 A Composition According to The Invention Having VaryingContent of a Hydrophilic Release-Modifying Agent

Samples were prepared as in Example 1 but with an addition ofmethylcellulose from Fluka (Product no. 64632). Prior to use, themethylcellulose was dissolved in de-ionised water at a concentration of50 g per litre of water. The solution was heated to 70° C. to speed upthe dissolution of methylcellulose. It is contemplated that a saturatedmethylcellulose-water gel is located in the micro-porosity of thecalcium sulphate structure during curing of the pastes, and inhibit ordelay diffusion of the active substance through the micro-porousstructure. A similar effect may be achieved by using methylcellulose ina micronised form (having a particle size in the micron area or less).

Compositions with 6 and 14% of cellulose as measured by weight wereprepared.

Composition 3 concentration in the final Ingredient amount (g)composition (% w/w) Calcium sulphate 0.266 53.2 Hydroxyflutamide 0.0040.8 Methylcellulose 0.030 6.0 Water 0.200 40.0

Composition 4 concentration in the final Ingredient amount (g)composition (% w/w) Calcium sulphate 0.226 45.2 Hydroxyflutamide 0.0040.8 Methylcellulose 0.070 14.0 Water 0.200 40.0

After 4 days, the release was reduced (cf. Example 1) to about 16% forthe composition with 6% methylcellulose, and to 14% for the samples with14% cellulose. After 15 days the release is about 50%, i.e. of the sameorder of magnitude as for the compositions without cellulose in Example1.

It is contemplated that methylcellulose is entrapped in the porousstructure of calcium sulphate and hinders the diffusion of the HF duringan initial stage, but with time also methylcellulose is dissolved in thesaline solution and, accordingly, the diffusion hindrance caused by thecellulose ceases.

In conclusion, a water-soluble, but slowly soluble, substance may beused as a release-modifying agent, especially, if it is desired todecrease the initial release rate.

Further tests are focused on the absorption of water into the porosityof cured pellets, as a measure of the water penetration of thecomposition.

Example 3 A Composition According to the Invention Having VaryingContent of a Hydrophobic Release-Modifying Agent

Pellets were prepared as in Example 1. The compositions include calciumsulphate hemi-hydrate, de-ionised water and silicone oil of viscosity12.500 cp (type Med 420 from Nusil Technology). The oil was firstdispersed in the de-ionised water by heavy shaking, and furtherdistributed during the massaging of the formed paste.

Water absorption was evaluated as the increase in weight of the pelletsbefore and after soaking for 10 minutes in de-ionised water, andcarefully dried on a paper tissue.

Compositions were prepared with two different silicone oil contents: 1%and 10% as measured by weight.

Composition 5 concentration in the final Ingredient amount (g)composition (% w/w) Calcium sulphate 0.391 78.2 Hydroxyflutamide 0.0040.8 Silicone oil 0.005 1.00 Water 0.100 20.0

Composition 6 concentration in the final Ingredient amount (g)composition (% w/w) Calcium sulphate 0.346 69.2 Hydroxyflutamide 0.0040.8 Silicone oil 0.050 10.0 Water 0.100 20.0

The pellets were first cured for 1 hr and thereafter left to dry for 24hrs in a silica gel autoclave before testing of water absorption.

A pellet without silicon oil absorbs between 23% and 40% of water asmeasured by volume and related to the volume of a pellet. An amountcorresponding to 1% w/w of silicone oil did not affect the waterabsorption measurably in these tests. An amount corresponding to 10% w/wof oil however reduced the water absorption significantly to 5-10% asmeasured by volume.

It is believed that the silicone oil, if well dispersed fills theporosity of the cured pellets and repels water to penetrate.

Accordingly, the release of the active substance from the cured pelletsis decreased compared to the results obtained in Example 2 using ahydrophilic release-modifying agent. In conclusion, a hydrophobicrelease-modifying agent may be used to decrease the release rate duringa long period of time.

Example 4 A Composition According to the Invention Having VaryingContent of a Low Solubility Hydrophilic Release-Modifying Agent

Pellets were prepared as in Example 3, but without the oil. Instead 6%and 18% calcium silicate (corresponding to 10 and 30% by weight asrelated to the calcium sulphate powder) was added to the compositions.The following compositions were made:

Composition 7 concentration in the final Ingredient amount (g)composition (% w/w) Calcium sulphate 0.266 53.2 Hydroxyflutamide 0.0040.8 Calcium silicate 0.030 6.0 Water 0.200 40.0

Composition 8 concentration in the final Ingredient amount (g)composition (% w/w) Calcium sulphate 0.206 41.2 Hydroxyflutamide 0.0040.8 Calcium silicate 0.090 18.0 Water 0.200 40.0

The same water absorption test as in Example 3 revealed that addition ofcalcium silicate reduced the water absorption to about 25-30% for thecompositions with 6% w/w of calcium silicate, and to about 15-20% forthe samples with 30% w/w of calcium silicate.

Due to the high water binding capability, calcium silicate will reactwith water and form an insoluble hydrate in the form of crystals. Thesecrystals or otherwise precipitated materials locate in the porousstructure of the cured calcium sulphate pellet.

In conclusion, a hydrophilic and strongly water binding hydratingceramic substance that may be transformed into a poor water-solublehydrate substance can be used as an alternative to the hydrophobicsubstances (such as silicone oil mentioned above) as a release modifyingagent.

Example 5 Composition According to the Invention Containing a FoamingAgent

Paste of only calcium sulphate and 40% water were prepared as in Example1 with 40% water. To 0.5 g of the paste 1 mg of sodium bicarbonate wasadded and mixed thoroughly. The paste was left to cure. During curing afoam-like structure was formed. This is the result of the bicarbonategenerating gas, as it is wetted.

The macroscopic appearance of this foamed material was characterised byopenings having a size in the range of 0.5-1.5 mm and an overallporosity of 60-80%. This open structure is at a much larger scale thanthe micro-porosity obtained in examples 1-4 (relating to the calciumsulphate itself), see FIGS. 1 and 2 herein.

Accordingly, it is possible to obtain a larger apparent surface area ofthe calcium sulphate pellet and thereby, adjusting the surface areaexposed to body fluids and in turn to erosion after administration to abody.

Example 6 Composition According to the Invention Containing a FoamingAgent

Paste of only calcium sulphate and water were prepared as in Example 1with 40% water. To 0.5 g of the pastes 10 mg of water peroxide (30%concentration from Fluka) was added. The paste was left to cure; afoam-like structure was formed.

Similarly as in Example 5, the macroscopic porosity of this foamedmaterial was characterised by openings in the range of 0.5-1.5 mm and anoverall porosity of 60-80%.

Example 7 Erosions Rates of Composition According to the Invention

The erosion/dissolution rate over time was measured for bodies kept insaline solution (9 mg/ml) at room temperature for three differentcompositions. The first composition (A) was prepared from calciumsulphate and water in the proportions 3 units of powder to 2 units ofwater by mass. This creates a structure similar to that in FIG. 1.

A second composition (B) based on the above composition (A) but with 1mg of sodium bi-carbonate was prepared. This composition has a largeopen porosity characterised by pores in the range of 0.5-1.5 mm indiameter. The structure is similar to that in FIG. 2.

A third composition (C) was prepared based on the composition (A) butwith an addition of 10 mg of silicon oil of 12500 cp viscosity (type Med420 from Nusil Technology).

From these compositions flat coins of 15 mm diameter and a thickness of2.0 mm were shaped and left to cure for 10 hrs. The coins were left in50 ml tubes with saline (9 mg/ml). The dissolution of the coins wasmeasured by weighing after 24 hrs, 48 hrs, 4 days and 7 days. Prior toeach measurement the coins were wetted and the exterior dried with a drytissue. The relative weight losses were as follows:

Composition Weight start 24 hrs 48 hrs 4 days 7 days A 1 0.988 0.9370.915 0.889 B 1 0.932 0.853 0.753 0.655 C 1 0.990 0.947 0.922 0.900

The experiments show that the larger surface area of an open ordisintegrated structure provides a higher dissolution/erosion rate. Theexample also illustrates that the addition of silicon oil, which reducesthe water up-take as illustrated in Example 3, has a very small effecton the erosion rate. Accordingly, sealing of the micro-porous structureof a ceramic and thereby avoiding leakage of any active substance therefrom, is an appropriate means to control the overall release of activesubstance from the composition, namely by means of erosion.

Example 8 Method to Evaluate Release Rates from the Compositions

This example describes a suitable method for the evaluation of therelease rate from compositions of the invention.

Composition according to example 1, composition 2, with three different2-hydroxyflutamide (HT) concentrations, was tested in a dog study. Theconcentration profile of HT in prostate tissue in male dogs after localadministration of the composition was investigated at different timepoints. Also a reference implant without HT was implanted in one dog.

Three male dogs are given 30, 60 or 120 mg of 2-hydroxy-flutamide bylocal implant delivery system in the prostate tissue; the totalimplantation time was 3 weeks.

The implant drug delivery system was inserted locally into the prostatetissue through sterile needles during rectal ultrasound guidance. Theanimals were under anesthesia during the insertion procedure.

Blood samples were taken every day for the first week and then once aweek for the remaining weeks. Plasma samples were collected in tubeswith EDTA and the plasma were transferred to microtubes of 2 ml,(sterile kryotubes from Sarstedt; No. 694.005).

The quantification of the parent drug, 2-hydroxyflutamide, in the plasmaand tissue samples, was done by HPLC-MS analysis.

The graphs in FIG. 3 show the plasma concentrations of2-hydroxyflutamide in dog plasma after three different doses of2-hydroxyflutamide as an implant in dog prostate tissue (H2, H3 and H4).Dog 1 (H1) was used as control and was only dosed an implant without2-hydroxyflutamide.

The extended plasma profiles over 3-6 days shows, that the release ratesof 2-hydroxyflutamide correlate well with in-vitro release rates inExample 1.

1-55. (canceled)
 56. A pharmaceutical composition comprising i) one ormore biodegradable hydrating ceramics ii) one or more expandable agents,iii) a sorbed aqueous medium, and iv) one or more therapeutically,prophylactically and/or diagnostically active substances.
 57. Apharmaceutical composition according to claim 56, wherein the one ormore therapeutically, prophylactically and/or diagnostically activesubstances is an androgen or a derivative thereof, an anti-androgen or aderivative thereof, an oestrogen or a derivative thereof, ananti-oestrogen or a derivative thereof, a gestagen or a derivativethereof, an anti-gestagen or a derivative thereof, an oligonucleotide, aprogestagen or a derivative thereof, a gonadotropin-releasing hormone oran analogue or derivative thereof, a gonadotropin inhibitor or aderivative thereof, an adrenal and/or prostate enzyme inhibitor, amembrane efflux and/or membrane transport protein, an immune systemmodulator, an angiogenesis inhibitor, or combinations thereof.
 58. Apharmaceutical composition according to claim 56, which in solid formhas a ruptured structure.
 59. A pharmaceutical composition according toclaim 56, wherein the active substance is flutamide, hydroxy-flutamide,cyproteron, nilutamide or bicalutamide or a mixture thereof.
 60. Apharmaceutical composition according to claim 56, wherein the activesubstance is a combination of an anti-androgen and agonadotropin-releasing hormone or an analogue thereof.
 61. Apharmaceutical composition according to claim 56, which in solid formhas a foam-like structure with openings, wherein at least 50% or more ofthe openings have a maximum width of at least about 0.1 mm.
 62. Apharmaceutical composition according to claim 56, wherein thebiodegradable hydrating ceramic is selected from the group consisting ofnon-hydrated or hydrated calcium sulphate, calcium phosphate, calciumcarbonate, calcium fluoride, calcium silicate, magnesium sulphate,magnesium phosphate, magnesium carbonate, magnesium fluoride, magnesiumsilicate, barium sulphate, barium phosphate, barium carbonate, bariumfluoride, barium silicate, or mixtures thereof.
 63. A pharmaceuticalcomposition according to claim 56, wherein the expandable agent is agas-forming agent, a swelling agent, a gelling agent or a disintegrant.64. A pharmaceutical composition according to claim 56, wherein theconcentration of the expandable agent in the composition is at leastabout 0.1% w/w.
 65. A pharmaceutical composition according to claim 56,wherein the concentration of sorbed aqueous medium is at the most about60% w/w of the total composition.
 66. A pharmaceutical compositionaccording to claim 56, wherein the composition is configured forparenteral use.
 67. A pharmaceutical composition according to claim 56,wherein the one or more biodegradable hydrating ceramics have amicroporous structure.
 68. A pharmaceutical composition according toclaim 56, wherein the active substance is controlled released from thecomposition.
 69. A composition in particulate form for use in thepreparation of a pharmaceutical composition as defined in claim 1, thecomposition comprising: i) one or more biodegradable hydrating ceramicsin powder form; ii) one or more expandable agents; and iii) optionally,one or more therapeutically, prophylactically and/or diagnosticallyactive substances.
 70. A method for treatment of a subject sufferingfrom a prostate disease, comprising administering to the subject acomposition comprising: i) one or more biodegradable hydrating ceramics;ii) one or more expandable agents; iii) sorbed aqueous medium; and iv)one or more therapeutically, prophylactically and/or diagnosticallyactive substances.
 71. A method according to claim 70, wherein theprostate disease is prostate cancer or prostate hyperplasia.
 72. Amethod according to claim 70, wherein the active substance is flutamide,hydroxy-flutamide, cyproteron, nilutamide or bicalutamide or a mixturethereof.
 73. A method according to claim 70, wherein the activesubstance is a combination of an anti-androgen and agonadotropin-releasing hormone or an analogue thereof.
 74. A methodaccording to claim 70, wherein the active substance is hydroxyflutamide.75. A method according to claim 70, wherein the composition isadministered to a subject's prostate tissue by implantation.